Studies in the laboratory of the principal investigator have shown that among amino acids in plasma the concentrations of alanine and the branched-chain amino acids (leucine, isoleucine, and valine) are most responsive to total starvation and protein deprivation in man. The studies of the mechanisms of these responses have included investigations of tissue pool sizes, transport, transamination, and oxidation of branched-chain amino acids in starved and protein-deprived rats. Total starvation promptly affects tissue transport, transamination, and oxidation of branched-chain amino acids, while protein deprivation for a brief period does not have a remarkable effect on these processes. The above studies have also established the skeletal muscle as an important adaptive organ in regard to fuel metabolism with its own unique ultrastructural and biochemical changes. We plan to investigate the magnitude and duration of variation in dietary caloric, protein, fat, and branched-chain amino acid content which is required to alter the metabolism of branched-chain amino acids in rats. The investigations will include determinations of tissue pool sizes, transport, transamination, oxidation, and metabolic conversions of branched-chain amino acids. In addition to starvation, obesity and diabetes also alter the metabolism of branched-chain amino acids. Therefore, we also plan to investigate the biochemical and physiological processes involved in the metabolism of branched-chain amino acids in rats made diabetic by streptozotocin and made obese by ventromedial hypothalamic lesions. The relevance of findings in animal models to common clinical problems in man will be investigated by in vivo and in vitro studies of branched-chain amino acids in human subjects before and after treatment for obesity. In view of the importance of muscle in caloric expenditure, in vitro studies in man will emphasize the effect of obesity on oxidation of metabolic fuels in this tissue.